3,4-二氢喹啉-2(1H)-酮衍生物的设计合成及抗精神分裂活性研究  

Design,synthesis and anti-schizophrenia activity of 3,4-dihydroquinolin-2(1H)-one derivatives

作　　者：辜顺林[1] 马志龙[1] 李亚莉[1] 俞蕾平[2] 李建其[1] 

机构地区：[1]上海医药工业研究院,上海200040 [2]中国科学院上海药物研究所,上海201203

出　　处：《中国药物化学杂志》2011年第2期81-87,共7页Chinese Journal of Medicinal Chemistry

基　　金：国家十一五"重大新药创制"资助项目(2009ZX09103-048)

摘　　要：目的设计合成3,4-二氢喹啉-2（1H）-酮类化合物,考察其对D2、5-HT2A、5-HT1A受体的亲和力,并对代表化合物进行体内抗精神分裂活性测试。方法 7-羟基-3,4-二氢喹啉-2（1H）-酮与二卤代烷进行O-烷基化反应,再与相应的哌啶衍生物反应得到目标产物（Ⅰ1~Ⅰ11）;对目标化合物进行了D2、5-HT2A、5-HT1A受体亲和力初步试验,并选择化合物Ⅰ7进行体内抗阿朴吗啡诱导的小鼠精神分裂模型实验。结果与结论共合成了11个新化合物,其结构经质谱及核磁共振氢谱确证。其中化合物Ⅰ7体内外活性良好,具有进一步研究的价值。7-Aminoalkyloxy-3,4-dihydroquinolin-2（1H）-ones have D2 receptor affinity,and aromatic heterocyclic piperidines or piperazines have 5-HT2A and 5-HT1A affinity,These two fragments were introduced to one structure,with a public nitrogen atom.Eleven new 3,4-dihydroquinolin-2（1H）-one derivatives were designed and synthesized.This new serial compounds were prepared by the following method：7-hydroxyl-3,4-dihydroquinolin-2（1H）-one was reacted with dihalides as O-alkylation reaction to yield Ⅲ,and then the target compounds were prepared by Ⅲ and corresponding piperidine derivatives（Ⅰ1-Ⅰ11）.The in vitro activities to D2,5-HT2A,5-HT1A receptors were tested for target compounds,their binding affinities to D2 and 5-HT1A are about 1-100 nmol · L-1,and to 5-HT2A are about 1-10 nmol · L-1.Their in vivo activity of apomorphine-induced stereotype in mice for representative compound Ⅰ7 were also tested,and it showed high inhibitory rate（70.23%） at 0.35 mg · kg-1（p.o.）.Preliminary SAR indicates：The chain in the middle with three or four carbon atoms gives better activities to D2 and 5-HT2A,3-（piperazin-1-yl）benzo[d]isothiazole is more beneficial for 5-HT1A activity than 6-fluoro-3-（piperidin-4-yl）benzo[d]isoxazole.

关 键 词：3 4-二氢喹啉-2(1H)-酮 抗精神分裂 合成 

分 类 号：R914[医药卫生—药物化学]